Medication adherence rates among youth living with HIV (YLH) are inadequate to effectively manage the disease. Very few adherence interventions have been tested with youth, and those that have are difficult to implement in real-world settings due to high intensity of sessions or low attendance rates. Thus, there is a demand for innovative, feasible, and engaging behavioral interventions targeting adherence, especially among YLH, the largest initiators of antiretroviral treatment (ART). A universal primary prevention program is a novel approach to target adherence problems before they begin by providing a prevention intervention to all youth newly initiating ART. In response to PA-14-127, this proposal plans to test a brief, 2-session, computer-delivered motivational intervention to prevent adherence difficulties among youth newly prescribed ART. All elements of the protocol (assessment, intervention, control condition) were piloted in a small multi-site randomized controlled trial in the NIH-funded Adolescent Medicine Trials Medicine Network for HIV/AIDS interventions (ATN). Results suggested feasibility and acceptability of the study protocol as well as trends for improved adherence when comparing the intervention to an active control condition. For the proposed multi-site randomized clinical trial, youth newly beginning ART (N=300 from 4 ATN sites in the United States) will be randomize to the Motivational Enhancement System for Adherence (MESA) or to the control condition (nutrition and exercise information delivered by the same platform matched for dose). ART adherence (visual analog and hair specimen assays) and biomedical measures (viral load and CD4 counts), in addition to potential mediators (HIV knowledge, motivation for adherence, and self-efficacy for adherence) and moderators (substance abuse, mental health symptoms, executive functioning, and stressful life events) will be collected at baseline, 1-month, and 3-, 6-, 9- and 12-months. It is hypothesized that youth randomized to MESA will show significantly greater adherence and health outcomes than youth randomized to the control condition over one year of follow-up. In addition, we will identify the mechanisms (mediators) of MESA treatment effects on primary outcomes and assess predictors of differential intervention response including substance abuse, mental health symptoms, executive functioning, and structural barriers.